Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[N:27]([C:30]1[CH:31]=[C:32]([C:38]([F:41])([F:40])[F:39])[C:33]([C:36]#[N:37])=[N:34][CH:35]=1)=[C:28]=[S:29].Cl.C[OH:44]>CC(N(C)C)=O.CCOC(C)=O>[O:44]=[C:1]1[C:3]2([CH2:6][CH2:5][CH2:4]2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[C:28](=[S:29])[N:27]1[C:30]1[CH:31]=[C:32]([C:38]([F:41])([F:39])[F:40])[C:33]([C:36]#[N:37])=[N:34][CH:35]=1
Reactant: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC3(C#N)CCC3)cc2)CC1
Reactant: CO
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(N4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 4-(4-(1-cyanocyclobutylamino)phenyl)piperazine-1-carboxylate (Intermediate 86, 0.25 g, 0.70 mmol) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (Intermediate 10, 241 mg, 1.05 mmol) in DMA (5 mL) was heated to 80° C. for 12 h. 2M HCl/MeOH=1/1 (10 mL) was added then and the resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (3×), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by Prep-HPLC (20% acetonitrile in water) to afford 75 mg of 5-(8-oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile. 1H NMR (DMSO-d6, 300 MHz) δ 9.26 (s, 1H), 9.19 (m, 1H), 8.74 (m, 1H), 7.25 (d, 2H), 7.15 (d, 2H), 3.48 (m, 4H), 3.22 (m, 4H), 2.60-2.49 (m, 2H), 2.48-2.40 (m, 2H), 1.95 (m, 1H), 1.63 (m, 1H). LCMS [M+H]+ 487.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:11].C([C:15]([NH:17][C:18]#[N:19])=O)C>C(O)C>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH:11][CH:15]=[N:17][C:18]#[N:19]
Reactant: CCC(=O)NC#N
Reactant: CC1(C)Cc2ccccc2C1N
Solvent: CCO
Product: CC1(C)Cc2ccccc2C1NC=NC#N
Yield: 96 %

Procedure:
250 Parts of 2,3-dihydro-2,2-dimethyl-1H-inden-1-amine were dissolved in 80 parts of ethanol. 150 Parts of ethyl-N-cyanoformamidate were added within 10 minutes and the mixture was heated to reflux. The cooled solution was concentrated, the precipitate was filtered off and dried. yielding 316 parts (96%) of N-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-N'-cyanoformamidine; mp. 164-167° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][Cl:10]>>[Cl:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCCBr
Product: ClCCN1CCOCC1

Procedure:
Morpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 4-(2-chloroethyl)morpholine
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[CH2:15]([S:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]=[N:11][C:22]2[CH:21]=[C:20]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[OH:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCSc1ccc(O)c2ccccc12
Reactant: O=N[O-]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Product: CCCCSc1cc(N=Nc2ccc([N+](=O)[O-])cc2)c(O)c2ccccc12

Procedure:
This is prepared similarly to Example 1 using 1.3 g (9.46 mmoles) of 4-nitro-aniline, 0.72 g (10.3 mmoles) of sodium nitrite, and 2 g (8.6 mmoles) of 4-butylthio-1-naphthol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1)[CH2:25][OH:26]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: NC(CO)CO
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC=CC=1NC1C=CC=CC=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[N:8]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:9]1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: COc1ccccc1Nc1ccccc1
Agent: O=Cc1ccccn1
Product: COc1ccccc1-n1nnc(-c2ccccn2)n1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 2-methoxyphenylaniline (36.9 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(2-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].Cl>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C2CCCC2)Cc2cc(OCCCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A mixture of ethyl 6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate (16 g., 0.036 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50 ml.) is stirred and refluxed for 6 hours. The mixture is poured into ice water (500 g.), extracted with ether, dried over Na2SO4, filtered and concentrated to a volume of 100 ml., and chilled. A total of 11.5 of 6-[6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoic acid separates, m.p. 127°-129 °C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:25][CH2:26][CH2:27][OH:28]
Reactant: NCCO
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2-amino-ethanol. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (s, 1 H), 7.85-7.80 (d, J=8.4 Hz, 1 H), 7.80-7.75 (d, J=7.6 Hz, 1 H), 7.75-7.70 (d, J=7.2 Hz, 1 H), 7.61-7.50 (m, 3 H), 6.10 (s, 1 H), 5.48-5.39 (m, 1 H), 5.08-4.95 (m, 1 H), 4.80-4.70 (m, 1 H), 4.52-4.42 (m, 1 H), 3.88-3.80 (t, J=5.6 Hz, 2 H), 3.65-3.60 (t, J=5.6 Hz, 2 H), 3.59-3.40 (m, 2 H), 2.46 (s, 3 H).
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1.N1C=CC=CC=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>O>[Cl:29][CH2:30][C:31]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:32]
Reactant: CS(=O)(=O)Nc1cc(N)ccc1Oc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(NC(=O)CCl)ccc1Oc1ccccc1
Yield: 75.3 %

Procedure:
To 150 ml of a dichloromethane solution containing 15.0 g of N-(5-amino-2-phenoxyphenyl)methanesulfonamide and 4.7 g of pyridine was added 6.7 g of chloroacetyl chloride under ice-cooling, followed by stirring for an hour. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate-n-hexane to give 14.4 g of N-(5-chloroacetylamino-2-phenoxyphenyl)methanesulfonamide as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (1 mL) in anhydrous dichloromethane (3 mL) was added methanesulfonyl chloride (36 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 399.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.C[Si]([N:21]=[C:22]=[O:23])(C)C.Cl>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22]([NH2:21])=[O:23])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc2c(c1)CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Reaction time: 1 h
Yield: 32.6 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g., 0.05 mol.) in hexane (50 ml.) was cooled to 0° C and treated dropwise with 15w/w butyllithium in hexane (26 ml., 0.06 mol.) in a nitrogen atmosphere. The reaction mixture was allowed to stand at 0° C for 1 hour and was then added dropwise over 30 minutes to a solution of trimethylsilylisocyanate (19.5 g., 0.17 mol.) in hexane (50 ml.) keeping the internal temperature at -20° C. The reaction mixture was allowed to stand at -20° C for 1 hour and was then diluted with water (50 ml.) and the pH adjusted to 2.0 with conc. HCl. The hexane layer was separated and discarded and the aqueous solution adjusted to pH 10.0 with sodium carbonate and extracted with chloroform (3 × 25 ml.). The combined extracts were washed with saturated brine, dried and the solvent removed in vacuo. The residue was triturated with n-hexane, filtered and the solid crystallised from ethyl acetate to give the title compound as colourless needles (3.1 g., 35%) m.p. 104° C. identical in all respects to the authentic material (when crystallised from ethyl acetate). Analysis: Found C, 69.1; 7.4; N, 14.7. C11H14N2O requires C, 69.5; H, 7.4; N, 14.7. The hexane soluble material was distilled to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (4.2 g.) b.p. 120°/15 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH:29]=[C:17]1[C:18](=[O:21])[CH2:19][CH2:20][N:15]([C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:16]1)[CH3:28]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(COc2ncccc2N2CCC(=O)CC2)cc1
Product: COc1ccc(COc2ncccc2N2CCC(=O)C(=CN(C)C)C2)cc1

Procedure:
A solution of 2′-(4-methoxybenzyloxy)-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (962 mg, 3.08 mmol) in N,N-dimethylformamide-dimethylacetal (7.0 ml, 52.28 mmol) was heated at 75° C. for 21 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8% methanol in EtOAc) to give the title compound as an orange, viscous oil (628 mg, 56%).
Reaction SMILES: BrC1C=C2C(=CC=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C(C)=C2.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[CH2:40][C:41](=O)[CH3:42]>>[C:27]([O:26][C@@H:20]([C:7]1[C:41]([CH3:42])=[CH:40][C:34]2[C:35](=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[F:32])[C:8]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Cc1ccc(F)cc1F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(F)cc(F)cc2c1OS(=O)(=O)C(F)(F)F

Procedure:
(S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar was as (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate in Example 20, except using 1-(2,4-difluorophenyl)propan-2-one instead of 1-(3-bromophenyl)propan-2-one. 1H-NMR: 400 MHz, (CDCl3) δ: 7.82 (s, 1H), 7.39 (d, J=5.47 Hz, 1H), 6.99 (m, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 2.49 (s, 3H), 1.11 (s+t, 12H). 19F-NMR: 377 MHz, (CDCl3) δ: −73.27 (s, 3F), −109.1 (m, 1F), −117.5 (m, 1F).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].[BH4-].[Na+]>CC(C)=O.CO>[CH2:13]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH:12]=[CH2:11]
Reactant: c1cnc2ccncc2c1
Reactant: C=CCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: C=CCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (6.5 g, 0.05 mol) and allyl bromide (9.1 g, 0.075 mol) in acetone (50 ml) was refluxed for 8 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (300 ml) and sodium borohydride (18.9 g, 0.5 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane and benzene-chloroform (3:1)) and distilled, bp 98° C./1.0 mmHg, to afford the Compound No. 12 (5.70 g, 65.5%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:30][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: Cc1cccc(C=O)n1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1cccc(CNc2cccc3nc(NCc4ccc(C)o4)ccc23)n1

Procedure:
The title compound, MS: m/e=359.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 6-methyl-2-pyridinecarboxaldehyde as described in example 26.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37]C(C)(C)C)=[O:36].[ClH:45]>O1CCOCC1>[ClH:45].[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC4C(=O)Nc5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC4C(=O)Nc5ccccc54)CC3)C2=O)c1
Yield: 90 %

Procedure:
tert-Butyl 3-((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.29 g, 0.488 mmol) and 4M hydrochloric acid/1% triethylsilane in 1,4-dioxane (6 mL) were stirred at room temperature for 4 hours. The reaction was evaporated and the residue purified by PTLC (10% methanol/dichloromethane). The product obtained from PTLC was redissolved in 4M hydrochloric acid in dioxane and evaporated. The residue was dissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized to give product as a white solid (0.25 g, 90%); HPLC rt 9.32 min; NMR (DMSO-d6); δ1.82 (m, 4H); 1.89 (d, J=14 Hz, 2H); 2.94 (m, 2H); 3.16 (m, 2H); 3.44-3.54 (m, 5H); 4.64 (s, 4H); 6.79 (t, J=7.2 Hz, 1H); 6.84 (d, J=7.6 Hz, 1H); 6.97 (m, 1H); 7.01 (d, J=8.4 Hz, 2H); 7.17-7.23 (m, 3H); 7.32 (d, J=7.6 Hz, 1H); 7.49-7.58 (m, 2H); 7.87-7.89 (m, 2H); 10.38 (br s, 1H); 10.44 (s, 1H); 13.0 (br s, 1H); MS for C32H34N4O4 m/z 539 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[N+:5]([O-])=[C:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.P(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[N:5]=[C:6]([CH2:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)Cc1cc(Br)cc(CC(F)(F)F)n1

Procedure:
A solution of 4-bromo-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.1 g, 6.2 mmol) and PBr3 (1 mL) in CH2Cl2 (15 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice, made basic with 15% NaOH and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a pale yellow solid (1.77 g, 89%). 1H NMR (400 MHz, CDCl3): δ 3.59 (t, J=10.4 Hz, 4H), 7.51 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.N1CCOCC1>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:28])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)N5CCOCC5)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.06 g, 0.2 mmol), HATU (0.15 g, 0.40 mmol), N-methylmorpholine (0.04 mL, 0.6 mmol) and morpholine (0.1 mL, 1 mmol) in THF (4.0 mL) and DMF (1.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 3:1) to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(morpholin-4-yl)carbonyl]-8λ6-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (88) (0.05 g, 45%) as a tan solid. 1H NMR (DMSO-d6): δ 8.49 (s, 1H), 7.14 (s, 1H), 6.75 (s, 1H), 3.72-3.14 (m, 10H), 2.44 (m, 1H), 2.00 (d, 1H), 1.83 (d, 1H), 1.70-1.32 (m, 8H), 1.28-1.22 (m, 1H), 1.12 (m, 1H), 0.96 (m, 1H), 0.89 (s, 3H), 0.86 (m, 3H), 0.82 (m, 1H), 0.79 (s, 3H). MS m/z 476 (C26H37NO6S+H+).
Reaction SMILES: [NH:1]1[C:10](=[S:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].Br[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([S:11][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Nc1nc2nc[nH]c2c(=S)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SC(c2ccccc2)c2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 48.1 %

Procedure:
A mixture of thioguanine (25 g), bromodiphenylmethane (37.1 g) and potassium carbonate (31.1 g) in N,N-dimethylformamide (250 cm3) was stirred at ambient temperature for 66 hour. The reaction mixture was filtered and the filtrate evaporated to give a cream solid. Recrystallisation from methanol gave 24 g (48%) of the title compound, m.p. 226°-227° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.B1([O-])OO1.[OH2:27].[OH2:28].O.O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11]([CH3:12])(=[O:28])=[O:27])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: O
Reactant: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: C#CCN(C(=O)C(C)S(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 65 °C
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide (0.10 g, 0.30 mmol) and acetic acid (2.0 ml) was added sodium perborate tetrahydrate (0.11 g, 0.74 mmol) and the vial was heated to 65° C. for 2 h. The reaction mixture was cooled to ambient temperature and neutralized with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (0-20% MeOH/DCM) to afford the title compound as a yellow foam (84 mg, 0.21 mmol, 73%): 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54-7.39 (m, 1H), 4.89 (d, J=16.9 Hz, 1H), 4.20-4.08 (m, 1H), 4.07-3.92 (m, 1H), 3.01 (s, 3H), 2.34-2.29 (m, 1H), 1.67 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.97, 166.90, 148.77, 140.43, 140.24, 135.58, 129.36, 126.64, 124.14, 121.34, 73.80, 60.91, 38.78, 36.29, 13.97; ESIMS m/z 367 ([M+H]+).